This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The polycystic ovary syndrome (PCOS) is the leading cause of female infertility in the United States and is characterized by hyperandrogenism and chronic anovulation. The disorder affects approximately 6-10% of women of reproductive age. Women with PCOS are also at high risk for developing type 2 diabetes, presumably due to the insulin resistance that accompanies the syndrome. Some actions of insulin may be effected by putative inositolphosphoglycan (IPG) mediators of insulin action, and evidence suggests that a deficiency in a specific D-chiro-inositol (DCI)-containing IPG may contribute to insulin resistance in individuals with impaired glucose tolerance or type 2 diabetes mellitus. A deficiency in DCI may also contribute to the insulin resistance in women with PCOS. Previous studies of this research group demonstrated that women with PCOS, when compared to normal women, had an increase in the renal clearance of DCI, accompanied by a reduction in the circulating concentration of DCI and a decreased insulin-stimulated release of DCI-IPG during an oral glucose tolerance test (OGTT). Moreover, insulin sensitivity (as determined by frequently sampled intravenous glucose tolerance test [FSIVGTT]) correlated inversely with renal clearance of DCI. These findings are consistent with abnormal handling of DCI in PCOS that results in impaired release of the DCI-IPG mediator and, consequently, insulin resistance. However, in a subgroup analysis, increased urinary DCI clearance was only evident in obese women with PCOS, but not in obese normal women, or non-obese PCOS or normal women (see Preliminary Progress). In fact, obese women with PCOS had a 14 fold increase in renal clearance of DCI compared to obese normal women. Thus, it appears that obesity needs to be present for the abnormality in renal clearance of DCI to be present in PCOS, and obesity does not seem to have an effect in DCI renal clearance in normal women. Our hypothesis is that obesity modulates the renal clearance of DCI in women with PCOS, but not in normal women. A corollary of this hypothesis is that an increased urinary DCI clearance leads to a reduction in circulating DCI and insulin-stimulated DCI-IPG release, and aggravates insulin resistance in women with PCOS. To test our hypothesis, we propose to study the following specific aims: 5. Specific Aims Specific Aim 1: Determine if DCI renal clearance in obese women with PCOS is increased compared to age- and weight-matched, obese normal women. In this aim, we will reconfirm that obese women with PCOS have (i) increased renal clearance of DCI, (ii) decreased circulating levels of DCI, and (iii) decreased DCI-IPG release in blood during an OGTT, as compared to age- and BMI-matched, obese normal women. Specific Aim 2: Determine if weight loss reduces DCI renal clearance in obese women with PCOS, but not in age- and weight-matched obese normal women. This aim determines if weight loss reverses the abnormalities in DCI handling in PCOS. The effects of weight loss on (i) renal clearance of DCI, (ii) circulating levels of DCI, and (iii) DCI-IPG release in blood during an OGTT, will be compared between obese women with PCOS and age- and BMI-matched obese normal women. Specific Aim 3: Determine if a change (reduction) in DCI renal clearance as a result of weight loss is correlated with a change (improvement) in insulin sensitivity in obese women with PCOS that is independent of weight loss itself. In our previous studies, we have determined that insulin sensitivity has a significant inverse relationship with urinary DCI clearance. In this aim, we will determine if decreasing DCI renal clearance by weight loss in obese women with PCOS will improve insulin sensitivity and inflammatory risk markers independent of the degree of weight loss (via statistical adjustment with the degree of weight loss as a covariate). Specific Aim 4: Determine if an equivalent degree of weight loss in obese women with and without PCOS is associated with (i) a greater reduction in DCI renal clearance, and (ii) a greater improvement in insulin sensitivity in the PCOS women compared to the normal women. To further demonstrate whether improvement in insulin sensitivity as a result of an improvement in DCI handling is independent of weight loss itself, women will be stratified by the degree of weight loss. For each degree of weight loss, we will determine if obese women with PCOS have (i) a greater reduction of renal clearance of DCI and (ii) a greater improvement in insulin sensitivity and inflammatory risk markers as a result of weight reduction, as compared to weight-matched obese normal women. If our proposed studies confirm a role for obesity in modulating DCI handling in PCOS, they will substantially enhance our understanding of the pathogenesis of PCOS and are likely to provide insights into novel treatment strategies directed specifically at the IPG system and normalization of its function.